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Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for bone marrow failure or hematopoietic malignant diseases for Fanconi anemia (FA) patients. Although results have improved over the last decades, reaching more than 90% survival when a human leukocyte antigen (HLA)-identical donor is available, alternative HCT donors are still less reported. We compared HCT outcomes using HLA-mismatched unrelated donors (MMUD; n = 123) or haplo-identical donors (HDs), either using only in vivo T cell depletion (n = 33) or T cells depleted in vivo with some type of graft manipulation ex vivo (n = 59) performed for FA between 2000 and 2018. Overall survival (OS) by 24 months was 62% (53-71%) for MMUD, versus 80% (66-95%) for HDs with only in vivo T cell depletion and 60% (47-73%) for HDs with in vivo and ex vivo T cell depletion (p = .22). Event-free survival (EFS) was better for HD-transplanted FA patients with only in vivo T cell depletion 86% (73-99%) than for those transplanted from a MMUD 58% (48-68%) or those with graft manipulation 56% (42-69%) (p = .046). Grade II-IV acute graft-versus-host disease (GVHD) was 41% (MMUD) versus 40% (HDs with no graft manipulation) versus 17% (HDs with T cell depleted graft), (p = .005). No differences were found for the other transplant related outcomes. These data suggest that HDs might be considered as an alternative option for FA patients with better EFS using unmanipulated grafts., (© 2021 Wiley Periodicals LLC.)

The long-term evolution to intractable epilepsy in children treated with cyclosporine administered for graft-versus-host-disease after hematopoietic stem cell transplantation was evaluated. In a group of 185 children treated with cyclosporine after bone marrow transplantation, 15 (8%) presented with acute seizures that were generalized in 7 and focal in 7 and had absence status in 1. Electroencephalography (EEG) and neuroimaging showed predominant abnormalities in the occipital regions. One patient died shortly after the seizure; in seven cases, seizures remitted, whereas relapses were observed in seven others. After the first year, seizures persisted chronically in four cases and evolved to intractable epilepsy. Focal temporal epilepsy was diagnosed in three cases, whereas in the fourth case, a multifocal epilepsy was observed. Magnetic resonance imaging (MRI) detected mesial temporal sclerosis in all of these cases. The risk factors associated with evolution to epilepsy included lower age at transplantation (3-5 years), more than one relapsing seizure in the first year after transplantation, and longer treatment with cyclosporine. Not only can cyclosporine cause acute central nervous system toxicity, it can also determine intractable epilepsy associated with mesial temporal sclerosis.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only cure for juvenile myelomonocytic leukaemia (JMML), but relapse remains the major cause of failure. A second transplant may be considered a way to induce the graft vs. leukaemia effect in patients who relapse after their first HSCT. We describe a 7-month-old girl with JMML who relapsed after a first, related allo-HSCT, and who again relapsed 8 months after the second transplant, despite discontinuation of immusuppressive therapy. She underwent a third allogeneic transplant from another related donor. At the time of this report the patient is in complete remission 26 months after the third transplant. We suggest that a third allo-HSCT may be taken into consideration for JMML patients who experience relapse, even after two previous transplants.

Introduction: The Forkhead box protein P3 (FOXP3) is a transcription factor central to the function of regulatory T cells (Treg). Mutations in the FOXP3 gene lead to a systemic disease called immune dysregulation, polyendocrinopathy, and enteropathy, an X-linked syndrome (IPEX) characterized by the triad of early-onset intractable diarrhea, type 1 diabetes, and eczema. An atypical presentation of IPEX has been reported. Method: We report rare cases with equivocal clinical associations that included inflammatory, kidney, and hematologic involvements screened with massively parallel sequencing techniques. Results: Two patients with hemizygous mutations of FOXP3 [c.779T>A (p.L260Q)] and [c.1087A>G (p.I363V)] presented clinical manifestations not included in typical cases of IPEX: one was a 16-year-old male patient with an initial clinical diagnosis of autoimmune lymphoproliferative syndrome (ALPS) and who developed proteinuria and decreased kidney function due to membranous nephropathy, an autoimmune renal condition characterized by glomerular sub-epithelial antibodies. The second patient was a 2-year-old child with bone marrow failure who developed the same glomerular lesions of membranous nephropathy and received a bone marrow transplantation. High levels of IgG4 in serum, bone marrow, and kidney led to the definition of IgG4-related kidney disease (IgG4 RKD) in this young boy. The circulating Treg levels were normal in the former case and very low in the second. Conclusion: Two atypical associations of functional mutations of FOXP3 that include ALPS and IgG4 RKD are described. Membranous nephropathy leading to renal failure completed in both cases the clinical phenotypes that should be included in the clinical panorama of FOXP3 failure. [ABSTRACT FROM AUTHOR]

Highlights • In our cohort the incidence of SOS/VOD was 2%, and by applying the new pediatric EBMT criteria, all SOS/VOD were severe. • Age at HSCT < 2 years, Bu, female gender, and HLH increased the risk of SOS/VOD. • The OS at 1 year was lower in patients with SOS/VOD. • The NRM at 1 and 5 years was higher in patients with SOS/VOD. Abstract Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a potentially life-threatening complication that may develop after hematopoietic stem cell transplantation (HSCT). The aims of this retrospective multicenter study were to evaluate the incidence of SOS/VOD in a large cohort of children transplanted in centers across Italy by applying the new European Society for Blood and Marrow Transplantation (EBMT) criteria and to analyze the risk factors underlying this complication. We retrospectively reviewed data of pediatric HSCTs performed in 13 AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica)-affiliated centers between January 2000 and April 2016. The new pediatric EBMT criteria were retrospectively applied for diagnoses of SOS/VOD and severity grading. Among 5072 transplants considered at risk for SOS/VOD during the study period, 103 children (2%) developed SOS/VOD, and the grade was severe or very severe in all patients. The median time of SOS/VOD occurrence was 17 days after HSCT (range, 1 to 104). Sixty-nine patients (67%) were treated with defibrotide for a median time of 16 days (range, 4 to 104). In multivariable analysis age < 2 years, use of busulfan during the conditioning regimen, female gender, and hemophagocytic lymphohistiocytosis were risk factors statistically associated with the development of SOS/VOD. The overall mortality directly related to SOS/VOD was 15.5%. Overall survival at 1 year was worse in patients with SOS/VOD (P =.0033), and this difference disappeared 5 years after HSCT. Nonrelapse mortality was significantly higher 1 and 5 years after transplantation in patients who developed SOS/VOD (P <.001). Based on the application of new EBMT criteria, the overall incidence of SOS/VOD recorded in this large Italian pediatric retrospective study was 2%. Nonrelapse mortality was significantly higher in patients who developed SOS/VOD. Identifying the risk factors associated with SOS/VOD can lead to more effective early treatment strategies of this potentially fatal HSCT complication in childhood. [ABSTRACT FROM AUTHOR]

It is recognized that chimerism following hematopoietic stem cell transplantation (HSCT) is a dynamic process. The aims of this study were to describe the evolution of chimerism in children with nonmalignant diseases who underwent allogeneic HSCT, and to analyze the risk factors influencing chimerism status. A total of 101 HSCTs were performed in 85 patients with nonmalignant diseases. The donor was unrelated in 62.4% of HSCTs. Reduced-intensity conditioning (RIC) regimen was administered in 48.5% of patients. Acute graft-versus-host disease (aGVHD) occurred in 51.7% and chronic GVHD (cGVHD) in 39.7% of patients. Analysis of chimerism was performed through amplification of 9 specific short tandem repeats by polymerase chain reaction at engraftment and 1, 6, and 12 months after HSCT. Upon first evaluation, complete chimerism (CC) was detected in 34.7% and mixed chimerism (MC) in 55.4%, whereas graft failure occurred in 9.9% of patients. Severe aGVHD was associated with CC ( P  = .031). The last chimerism evaluation showed CC in 72.1%, stable MC in 12.8%, and progressive MC in 3.5%. CC was associated with a higher incidence of aGVHD ( P  = .016) and cGVHD ( P  = .022), whereas the RIC regimen was associated with graft failure ( P  = .026). One- and 3-year overall survival (OS) was 87.4% and 80.5%, respectively, with a lower OS at 3 years in patients with CC compared with those with MC ( P  = .008). aGVHD and cGVHD represent factors favoring CC, thus close, careful follow-up of chimerism is recommended in patients affected by nonmalignant disease. [ABSTRACT FROM AUTHOR]

Summary With improved outcome of allogeneic stem cell transplantation (allo-SCT) for hematologic malignancies, long-term complications gain greater importance. Skeletal complications such as osteoporosis or avascular necrosis (AVN) occur frequently in allogeneic recipients with a cumulative incidence of diminished bone mineral density of 24-50% between 2 and 12 months after allo-SCT and a cumulative incidence of AVN in as many as 19% of patients 3 years after allo-SCT. Here, we present a review as part of the German, Austrian, and Swiss Consensus Conference on clinical practice in chronic graft-versus-host disease, held 2009 in Regensburg. The Consensus Conference aimed to achieve a consensus on the current evidence of diagnosis, prevention, and therapeutic options of late complications after allo-SCT summarizing and discussing the literature on these topics. In this report, we provide recommendations for metabolic bone diseases agreed upon by the working party. This includes guidelines for diagnosis, prevention, and therapeutic options in patients with low bone mass or AVN. [ABSTRACT FROM AUTHOR]

Background. BK virus-associated hemorrhagic cystitis (BKV-HC) is a severe complication after allogeneic hematopoietic stem cell transplantation (HSCT), but antiviral treatment for this condition has not been evaluated. Methods. We conducted a retrospective survey on the safety and outcome of cidofovir treatment for patients with BKV-HC in centers affiliated with the European Group for Blood and Marrow Transplantation. Results. From 1 April 2004 to 31 December 2007, 62 patients received a diagnosis of BKV-HC after a median interval of 35 days after HSCT (range, 3-577 days). Fifty-seven patients (92%) received intravenous cidofovir, whereas 5 patients received cidofovir intravesically. Complete response (CR) was recorded in 38 (67%) of 57 patients with HC treated with intravenous cidofovir, whereas partial response (PR) was documented in 7 patients (12%). CR was documented in 3 patients and PR in 1 patient with HC treated with intravesical cidofovir. A reduction of 1-3 logs in BKV load was documented in 8 of the 10 patients achieving CR. Mild-to-moderate toxic effects were recorded in 18 of 57 patients who received intravenous cidofovir administration. In a multivariate analysis, the factors significantly associated with response to cidofovir were the stem cell source (P = .01) and the use of total body irradiation (Pp.03). After a median follow-up of 287 days, overall survival and total treatment-related mortality rates were 63% and 40% for patients achieving CR, compared with 14% and 72% for patients with PR or no response to cidofovir, respectively (P < .001 and P =.001, respectively). Conclusions. Cidofovir may be a potentially effective therapy for BKV-HC, but evidence supporting its use requires randomized controlled trials. [ABSTRACT FROM AUTHOR]

CEP is a rare inborn error of porphyrin–heme synthesis. Clinical manifestations can range from mild to severe and include erythrodontia, reddish-colored urine, and hemolytic anemia that can be mild or severe and may result in splenomegaly. Completely avoiding exposure to the sun is crucial. Attempts to reduce erythropoiesis and to lower circulating porphyrin levels by means of erythrocyte transfusions have been successful in reducing the expression of the disease. However, the complications of a chronic transfusion regimen are potentially severe. Successful bone marrow transplantation has been reported in CEP. We report a case of successful bone marrow transplantation and prolonged follow-up in an adolescent CEP patient. [ABSTRACT FROM AUTHOR]

To describe the incidence, risk factors, and treatment of autoimmune diseases (ADs) occurring after cord blood transplantation (CBT), we analyzed both CBT recipients reported to EUROCORD who had developed at least 1 new AD and those who had not. Fifty-two of 726 reported patients developed at least 1 AD within 212 days (range, 27-4267) after CBT Cumulative incidence of ADs after CBT was 5.0% ± 1% at 1 year and 6.6% ± 1% at 5 years. Patients developing ADs were younger and had more nonmalig-nant diseases (P < .001). ADs target hematopoietic (autoimmune hemolytic anemia, n = 20; Evans syndrome, n = 9; autoimmune thrombocytopenia, n = 11; and immune neutropenia, n = 1) and other tissues (thyroiditis, n = 3; psoriasis, n = 2; Graves disease, n = 1; membranous glomerulonephritis, n = 2; rheumatoid arthritis, n = 1; ulcerative colitis, n = 1; and systemic lupus erythematosus, n = 1). Four patients developed 2 ADs (3 cases of immune thrombocytopenia followed by autoimmune hemolytic anemia and 1 Evans syndrome with rheumatoid arthritis). By multivariate analysis, the main risk factor for developing an AD was nonmalignant disease as an indication for CBT (P = .0001). Hematologic ADs were most often treated with steroids, rituximab, and cyclosporine. With a median follow-up of 26 months (range, 2-91), 6 of 52 patients died as a consequence of ADs. We conclude that CBT may be followed by potentially life-threatening, mainly hematologic ADs. [ABSTRACT FROM AUTHOR]